Ribot & Silva-Santos Lab

Neuro-Immunology & Immuno-Oncology

Research developed in the Julie Ribot & Bruno Silva-Santos Joint lab, based on Cellular and Molecular Immunology, chases fundamental questions related to the biology of white blood cells (leukocytes). Two main research programs are running by two independent and cooperative group leaders:

Neuro-Immunology, run by Julie Ribot, that aims to dissect neuro-immune crosstalks, for example by considering the pathophysiological contributions of IL-17 beyond immune surveillance; and Immuno-Oncology, run by Bruno Silva-Santos, that investigates cellular and molecular interactions within the tumor microenvironment, with a focus on gamma-delta (γδ) T cells.

Neuro-Immunology

We are currently witnessing the emergence of a body of evidence that document novel functions of the immune system, interacting with other complex organ systems to maintain tissue homeostasis independently of pathogen challenge. Recent advances have now provided key findings that the immune system also acts as a tissue rheostat that continually senses homeostatic perturbations and contributes to organ steady state physiology.

We have recently identified a population of γδ T cells that infiltrate the lymphatics within the dura matter of the brain meninges. We demonstrated that this subset is a major source of IL-17, which promotes short-term memory by increasing neuronal synaptic plasticity in the hippocampus. On the other hand, we further reported a significant increase of meningeal IL-17 producing cells, which triggers the onset of cognitive decline in a mouse model of Alzheimer’s Disease. We thus postulate a dual role for IL-17: pro-cognitive at steady state and anti-cognitive in the context of neurodegeneration, and highlight that a tight regulation of the levels of meningeal IL-17 is critical to maintain brain integrity. These considerations led us to raise neuroscience questions under an innovative immunological angle:

• How are IL-17 levels finely tuned to guarantee optimal cognitive functions?

We are assessing the impact of environmental cues using diverse approaches such as system pharmacological manipulation, surgical ablation and specific genetic mouse models. As experimental read-out, we mostly use flow cytometry to analyze tissue immune landscape (focusing on IL-17 producers), as well as RNA sequencing to pioneer subset transcriptional profiling at single-cell resolution.

• What is the impact of IL-17 regulation on tissue pathophysiology?

We are unveiling novel neurophysiological processes under the regulation of IL-17 in the central and peripheral nervous system, namely focusing on learning and memory, anxiety, sleep and nerve regeneration. For this, we use genetic mouse models, microscopy, behavioral assays and electrophysiology.

Immuno-Oncology

In our Immuno-Oncology research line, which has been funded by the "la Caixa" Foundation, the European Molecular Biology Organization and Fundação para a Ciência e a Tecnologia, we study cellular and molecular crosstalks within the tumor microenvironment (TME), trying to boost anti-tumor mechanisms (based on cytotoxicity and interferon-gamma secretion) over pro-tumor effects (linked to inflammation and angiogenesis). Moreover, we have translated the seminal knowledge we produced on gamma-delta (γδ) T cells to the development of a new methodology for adoptive cell therapy of cancer – Delta One T (DOT) cells – within a spin-off company, Lymphact SA, acquired in 2018 by GammaDelta Therapeutics (London, UK), and now part of the Takeda immunotherapy portfolio. In our team, we continue to study DOT cells, their functional regulation and their molecular mechanisms of tumor cell recognition, in collaboration with Takeda.

We also conduct a more fundamental Immuno-Biology research line, which has been funded by Starting and Consolidator Grants from the European Research Council (ERC),where we focus on the thymic development and functional differentiation of gamma-delta (γδ) T cells. We aim to identify new molecular mechanisms involved in their thymic generation and in peripheral immune responses to infections (such as malaria) and cancer.

Research Team

Research Areas

• Neuroimmunology
• Tissue pathophysiology
• Immune regulation
• Immuno-Oncology
• Lymphocyte Differentiation

Ongoing Research Projects

2023/2026: Deciphering the role of IL-17 on peripheral nerve regeneration. Coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2023/ 2025: Optimizing Vdelta1 gamma-delta T cells for cancer immunotherapy. Coordinator: Bruno Silva-Santos. Funding Agency: Takeda, Inc.

2022/2023: Meningeal Immunity and NeuroInflammation: deciphering the immune cells intervening in neonatal bacterial meningitis. Co-coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2021/2024: Regulation of gamma-delta T cells in the tumor microenvironment. Coordinator: Bruno Silva-Santos. Funding Agency: Fundação para a Ciência e a Tecnologia.

2021/2024: Regulation of gamma-delta T cells in the tumor microenvironment. Coordinator: Bruno Silva-Santos. Funding Agency: Fundação para a Ciência e a Tecnologia.

2021/2024: Regulating meningeal γδ17 T cell homeostasis: Molecular mechanisms and pathophysiological implications. Coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2020/2023: Cellular and molecular regulators of multifaceted γδ T-cells in the tumor microenvironment. Coordinator: Bruno Silva- Santos. Funding Agency: Fundação AstraZeneca.

Previous Research Projects

2019/2022: Next-generation CAR-DOT cells for allogeneic adoptive cancer immunotherapy. Coordinator: Bruno Silva-Santos. Funding Agency: “la Caixa” Foundation.

2018/2021: PROMISE: Programação de células mielóides anti-tumorais para aplicação em imunoterapia do cancro. Coordinator: Karine Serre. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021: Impacto das células T gd17 residentes nas meninges em funções cognitivas num contexto fisiológico e neuropatológico. Coordinator: Julie Ribot. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021: Magiciam: um sistema imunodelador de macrófagos para prevenir a invasão e metastização das células tumorais. Co-Coordinator: Karine Serre. Funding Agency: Fundação para a Ciência e a Tecnologia.

2018/2021: Sub-therapeutic doses of ionizing radiation modulate the pre-metastatic niche and induce metastasis. Co-Coordinator: Karine Serre. Funding Agency: Fundação para a Ciência e a Tecnologia.

2015/2021: DevoTed_miR: MicroRNA determinants of the balance between effector and regulatory T cells in vivo. Coordinator: Bruno Silva-Santos. Funding Agency: European Commission.

Awards

Our team has been distinguished with:

• Scientific prize from Universidade de Lisboa (2021) awarded to Bruno Silva-Santos.
• Pfizer Award in Basic Research (2020), awarded to Julie Ribot and co-authors.
• Bruno Silva-Santos was elected Member of EMBO (European Molecular Biology Organization) in 2019.
• AstraZeneca Faz Ciência Award in Oncology (2019), awarded to Bruno Silva-Santos and Noella Lopes.
• Sociedade Portuguesa de Imunologia Best Paper Award 2019, awarded to Mensurado S, Rei M, Lança T, Ioannou M, Gonçalves-Sousa N, Kubo H, Malissen M, Papayannopoulos V, Serre K, Silva-Santos B.
• Prémio Janssen Inovação 2018, awarded to Sofia Mensurado, Karine Serre and Bruno Silva-Santos.
• Prémio BIAL de Medicina (2017) – 2nd Prize, awarded to Bruno Silva-Santos.
• Sociedade Portuguesa de Imunologia, Best Oral Presentation awarded to Julie Ribot.
• Scientific prize from Universidade de Lisboa (2016) awarded to Bruno Silva-Santos.
• INFARMED research award in oncoimmunology (Fundo de Investigação Saúde) awarded to Julie Ribot.
• Bruno Silva-Santos was nominated Honorary Member of the European Academy of Tumor Immunology in 2015.
• Bruno Silva-Santos was selected to the EMBO Young Investigator Programme (2010).
• 2nd Prize of the CESPU International Award (2010) to Julie Ribot, Ana de Barros and Bruno Silva-Santos.
• 2nd Young Investigator Award Prize of the International Cytokine Society (2009) to Bruno Silva-Santos.
• Pfizer Award in Clinical Research (2009) to Bruno Silva-Santos.
• Best Paper Award from the Portuguese Society of Immunology (2009) to Julie Ribot, Ana de Barros, Bruno Silva-Santos et al.
• 1st Postdoctoral Prize of the International Cytokine Society (2009) to Julie Ribot.

Selected Publications

Papotto PH, Yilmaz B, Pimenta G, Mensurado S, Cunha C, Fiala GJ, Gomes da Costa D, Gonçalves-Sousa N, Chan BHK, Blankenhaus B, Domingues RG, Carvalho T, Hepworth MR, Macpherson AJ, Allen JE, Silva-Santos B (2023). Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner. Cell Rep (2023):112074.

Mensurado S, Blanco-Domínguez R, Silva-Santos B (2023). The emerging roles of γδ T cells in cancer immunotherapy. Nat Rev Clin Oncol 20(3):178-191.

Darrigues J, Almeida V, Conti E and Ribot J.C. (2022). The multisensory regulation of unconventional T cell homeostasis. Seminars in Immunology 61-64:101657.

Gordino G, Pereira S, Corredeira P, Borges P, Costa L, Gomes A, Silva-Santos B and Ribot J.C. (2022). MicroRNA-181a restricts human γδ T cell functional differentiation by targeting Map3k2 and Notch2. EMBO Reports 23:e52234.

Sánchez Martínez D, Tirado N, Mensurado S, Martínez-Moreno A, Romecín P, Gutiérrez Agüera F, Correia DV, Silva-Santos B.*, Menéndez P* (2022). Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in acute myeloid leukemia. J Immunother Cancer 10(9):e005400.

Brigas H.C, Ribeiro M.R, Coelho J.R, Gomes R, Gomez V, Faivre E, Pereira S, Almeida AA, Buée L, Pousinha PA, Blum D, Silva-Santos B, Lopes L.V* and Ribot J.C*(2021). IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Reports 36, 109574.

Wilharm A*, Brigas HC*, Sandrock I, Ribeiro M, Amado T, Reinhardt A, Demera A, Hoenicke L, Strowig T, Carvalho T, Prinz I** and Ribot JC** (2021). Microbiota-dependent expansion of testicular IL-17-producing Vγ6+ γδ T cells upon puberty promotes local tissue immune surveillance. Mucosal Immunology 14:242–252.

Lopes N*, McIntyre C*, Martin S*, Raverdeau M*, Sumaria N, Kohlgruber A, Fiala G, Dyck L, Kellis M, Brenner M, Argüello RJ, Silva-Santos B**, Pennington DJ** and Lynch L** (2020). Distinct metabolic programs established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments. Nature Immunol 22, 179–192.

Ribot JC*, Lopes N* and Silva-Santos B (2020). γδ T cells in tissue physiology and surveillance. Nature Rev Immunol 21(4):221-232.

Ribeiro M*, Brigas HC*, Temido-Ferreira M, Omenetti S, Stockinger B, Waisman A, Lopes LV, Silva-Santos B and Ribot JC (2019). Meningeal γδ T cell–derived IL-17 controls synaptic plasticity and short-term memory. Science Immunol 4 (40): eaay5199.

Silva-Santos B*, Mensurado S and Coffelt SB* (2019). γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nature Rev Cancer 19(7):392-404. (*Corresponding authors)

Ribot JC*, Neres R*, Zuzarte-Luís V, Gomes AQ, Mancio-Silva L, Mensurado S, Pinto-Neves D, Carvalho T, Mota MM, Silva-Santos B and Pamplona A (2019). T cells promote IFN-dependent Plasmodium pathogenesis upon liver-stage infection. Proc Natl Acad Sci U S A 116(20):9979-9988.

Caiado F, Maia-Silva D, Jardim C, Carvalho T, Simões AE, Schmolka N, Schumacher TN, Norell H and Silva-Santos B (2019). Hypomethylating agents prevent chemoresistance in acute myeloid leukemia relapses by suppressing leukemia-initiating single-cell lineages. Nature Commun 10(1): 5451.

Di Lorenzo B*, Simões AE*, Caiado F, Tieppo P, da Silva MG, Déchanet-Merville J, Schumacher TN, Prinz I, Norell H, Ravens S, Vermijlen D and Silva-Santos B (2019). Broad cytotoxic targeting of acute myeloid leukemia by polyclonal Delta One T cells. Cancer Immunol Res 7(4):552-558.

Mensurado S, Rei M, Lança T, Ioannou M, Gonçalves-Sousa N, Kubo H, Malissen M, Papayannopoulos V, Serre K, Silva-Santos B (2018). Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress. PLoS Biology 16(5):e2004990.

Schmolka N, Papotto PH, Romero PV, Amado T, Enguita FJ, Amorim A, Rodrigues AF, Gordon KE, Coroadinha AS, Boldin M, Serre K, Buck AH, Gomes AQ and Silva-Santos B (2018). MicroRNA-146a controls functional plasticity in γδ T cells by targeting Nod1. Science Immunol: 3(23): pii: eaao1392.

Papotto PR*, Ribot JC* and Silva-Santos B (2017). IL-17+ γδ T cells as kick-starters of inflammation. Nature Immunol 18(6):604-611. Review.

Ribeiro ST, Tesio M, Ribot JC, MacIntyre E, Barata JT and Silva-Santos B (2017). Casein kinase 2 controls the survival of normal thymic and leukemic γδ T cells via promotion of AKT signaling. Leukemia Dec 16, doi: 10.1038/leu.2016.363.

Almeida AA, Correia DV, da Silva CL, da Silva MG, Anjos DR and Silva-Santos B (2016). Delta One T cells for immunotherapy of chronic lymphocytic leukemia: clinical-grade expansion/ differentiation and preclinical proof-of-concept. Clin Cancer Res 22(23):5795-5804.

Muñoz-Ruiz M, Ribot JC, Grosso AR, Gonçalves-Sousa N, Pamplona A, Pennington DJ, Regueiro JR, Fernandez-Malavé E and Silva-Santos B (2016). TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets. Nature Immunol 17:721-7.

Ribot J.C, Ribeiro S.T, Sousa A.E, Silva-Santos B (2014). Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. The Journal of Immunology 192(5): 2237-43.

Schmolka N*, Serre K*, Grosso AR, Rei M, Pennington DJ, Gomes AQ and Silva-Santos B (2013). Epigenetic and transcriptional signatures of stable versus plastic differentiation of pro-inflammatory γδ T cell subsets. Nature Immunol 14(10):1093-100.

Coquet J.M*, Ribot J.C*, Middendorp S., van der Horst G., Xiao Y., Pennington D.J., Silva-Santos B and Borst J (2013). CD70 on dendritic and epithelial cells in the thymic medulla promotes CD4+ regulatory T cell development via CD27. The Journal of Experimental Medicine 210(4) 715-28.

Correia DV, Fogli M, Hudspeth K, da Silva MG, Mavilio D and Silva-Santos B (2011). Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells. Blood 118(4):992-1001.

Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Girardi M, Borst J, Hayday AC, Pennington DJ and Silva-Santos B (2009). CD27 is a thymic determinant of the balance between IFN-γ- and IL-17-producing γδ T cell subsets. Nature Immunol 10(4): 427-36.

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